The use of predictive and prognostic biomarkers paired with targeted cancer therapies may hold the key to reducing drug development time, improving drug efficacy, and guiding clinical decision making. While there are advances in cancer treatment, chemotherapy remains largely inefficient and ineffective. One reason for the generally poor performance of chemotherapy is that the selected treatment is often not closely matched to the individual patient's disease. A personalized medicine approach that couples precision diagnostics with therapeutics, especially targeted therapeutics, is considered a highly promising method for enhancement of the effectiveness of current and future drugs. Biomarkers can facilitate the development and use of such targeted therapeutics as well as standard of care therapies.
To date there are only a handful of biomarkers that have added value to clinical oncology practice. In part this is because perceived markers often are correlative but not causal to drug mechanism. Even when the “biomarker” biology does line up with the pharmacology of the companion therapy there is still significant challenge to predicting how a drug will work in a patient. Beyond this, the path to clinical development requires the participation of physician-scientists who see the value of the test and believe it can bring benefit to their patients.
Chemotherapy used in the treatment of cancers can induce apoptosis of the tumor cells. Apoptosis is a process of programmed cell death mediated by a number of signaling pathways that converge at the mitochondria and is effected by caspases, a group of cytosolic proteins. These proteins are activated through a series of biochemical events and the terminal caspase activating event can be blocked by proteins called the inhibitors of apoptosis (IAPs) which can prevent apoptosis and block drug response in cancer patients. Inhibitor of apoptosis proteins (IAPs) suppresse apoptosis through binding and inhibiting active caspases-3, -7 and -9 via its baculoviral IAP repeat (BIR) domains. Caspase inhibition by IAPs can be negatively regulated by a mitochondrial protein second mitochondrial-derived activator of caspase (SMAC). SMAC physically interacts with multiple IAPs and relieves their inhibitory effect on caspases-3, -7 and -9. A new class of treatment that mimics the function of the protein SMAC, perturbs the IAP function and activates the otherwise blocked caspase, thereby allowing apopotosis to be induced in a cell.
Further, apoptosis can be regulated by the Bcl-2 proteins, a group of mitochondrial proteins. The response to the Bcl-2 family members in a cell is in part regulated by dimerization domains within this family. More specifically, pro-apoptotic and anti-apoptotic Bcl-2 proteins form heterodimers with their cognate regulating Bcl-2 proteins (i.e., the BH3-only Bcl-2 proteins), thereby executing cell death or survival signals. For example, the ability of Bcl-2 to inhibit apoptosis is blocked by the formation of a heterodimer with Bax (Yang and Korsmeyer, 1996).
Essentially all effective cancer drugs induce apoptosis in target cancer cells. However, different cancer cells respond to an apoptosis-inducing drug in different manners. This can be due to the presence of different heterodimers between the caspases and the IAPs or the Bcl-2 heterodimers with their cognates. Determining the presence of these heterodimers in a cancer patient can then help in assessing that patient's responsiveness to an apoptosis-inducing cancer drug.